This proposal seeks to elucidate cross-level coupling (CLC) in multi-scale brain networks - that is, characterizing interactions between different spatial and temporal levels of brain organization, with a particular focus on the connection between spiking in single neurons and the distributed activity of the large-scale, dynamic functional networks in which they are embedded. This project will clarify the nature of multi-scale coupling and investigate causal mechanisms by which these interactions can be controlled. A key motivation for this research is that multi-scale CLC may provide a novel route for rehabilitative therapies and the design of new devices for clinical intervention following traumatic brain injury or stroke. Importantly, this project employs the real-time, chronic, multi-site, high-density microelectrode array recording techniques used in brain-machine interface (BMI) research combined with novel modeling and analysis methods. This approach was recently used to demonstrate that oscillatory phase coupling between multiple brain areas coordinates the spiking of single neurons as well as anatomically-dispersed functional cell assemblies (Canolty, et al., 2010, PNAS). These results, showing that dynamic patterns of large-scale network activity may serve to regulate neuronal ensembles, provide a striking example of functional interactions in multi-scale brain networks. This proposal builds on these results with the aim of further characterizing the functional role of interactions in multi-scale brain networks, their dependence on task conditions and various other experimental manipulations, and investigates the potential for external control of CLC via causal intervention using electrical stimulation. The first specific aim, targeting characterization of CLC, investigates how CLC in multi-scale brain networks changes across different behavioral tasks, between distinct neuronal groups, over extended periods of learning, and under pressure from operant conditioning. The second aim, targeting control of CLC, investigates the feasibility of using electrical stimulation to directly map network connectivity and causally influence neuronal activity and behavior by entraining different patterns of oscillatory network coupling. Together, these two aims provide the focus for a vigorous new research agenda targeting the exciting but poorly understood phenomenon of CLC in ways that may prove immediately useful in the development of effective clinical applications. PUBLIC HEALTH RELEVANCE: A greater understanding of the mechanisms and functions of cross-level coupling (CLC) in multi-scale brain networks - together with methods by which it can be controlled - will facilitate the development of stimulation- based clinical devices and rehabilitative therapies to aid recovery following traumatic brain injury or stroke. This project is therefore positioned to provide answers to fundamental questions in neuroscience concerning the dynamics of multi-scale brain networks while simultaneously improving the quality of life for large numbers of neurological patients.